Vitamin D and Parathyroid Hormone Actions

7-dehydrocholesterol

PTH Hypercalcemia

PTHrP Hyperphosphatemia

Hypophosphatemia 1, 25(OH)2D3

Hypocalcemia Acidosis

24R, 25(OH)2D3

7-dehydrocholesterol

25-hydroxylase

25-hydroxy-vitamin D0

1-alpha- 24-hydroxylase hydroxylase

25-hydroxylase

25-hydroxy-vitamin D0

Hypercalcemia

Hyperphosphatemia

IGF-1

PTH Hypercalcemia

PTHrP Hyperphosphatemia

Hypophosphatemia 1, 25(OH)2D3

Hypocalcemia Acidosis

24R, 25(OH)2D3

OH

^Various tissue enzymes Hydroxylated and conjugated polar metabolites

1-alpha- 24-hydroxylase hydroxylase

Kidney, intestine, other tissue

^Various tissue enzymes Hydroxylated and conjugated polar metabolites

Hypercalcemia

Hyperphosphatemia

Kidney, intestine, other tissue

24, 25-hydroxy-vitamin D,

24, 25-hydroxy-vitamin D,

FIGURE 5-3

Metabolism of vitamin D. The compound 7-dehydrocholesterol, through the effects of heat (37°C) and (UV) light (wavelength 280-305 nm), is converted into vitamin D3 in the skin. Vitamin D3 is then transported on vitamin D binding proteins (VDBP) to the liver. In the liver, vitamin D3 is converted to 25-hydroxy-vitamin D3 by the hepatic microsomal and mitochondrial cytochrome P450-containing vitamin D3 25-hydroxylase enzyme. The 25-hydroxy-vitamin D3 is transported on VDBP to the proximal tubular cells of the kidney, where it is converted to 1,25-dihydroxy-vita-min D3 by a 1-a-hydroxylase enzyme, which also is a cytochrome P450-containing enzyme. The genetic information for this enzyme is encoded on the 12q14 chromosome. Alternatively, 25-hydroxy-vitamin D3 can be converted to 24R,25-dihydroxy-vitamin D3, a relatively inactive vitamin D metabolite. 1,25-dihydroxy-vitamin D3 can then be transported by VDBP to its most important target tissues in the distal tubular cells of the kidney, intestinal epithelial cells, parathyroid cells, and bone cells. VDBP is a 58 kD a-globulin that is a member of the albumin and a-fetoprotein gene family. The DNA sequence that encodes for this protein is on chromosome 4q11-13. 1,25-dihydroxy-vitamin D3 is eventually metabolized to hydroxylated and conjugated polar metabolites in the enterohepatic circulation. Occasionally, 1,25-dihydroxy-vitamin D3 also may be produced in extrarenal sites, such as monocyte-derived cells, and may have an antiproliferative effect in certain lymphocytes and keratinocytes [1,7-9]. (Adapted from Kumar [1].)

Oral calcium intake ~1000 mg/d

Oral calcium intake ~1000 mg/d

Bone

200 mg

Bone

200 mg

FIGURE 5-4

Calcium (Ca) flux between body compartments. Ca balance is a complex process involving bone, intestinal absorption of dietary Ca, and renal excretion of Ca. The parathyroid glands, by their production of parathyroid hormone, and the liver, through its participation in vitamin D metabolism, also are integral organs in the maintenance of Ca balance. (From Kumar [1]; with permission.)

T-lymphocyte

T-lymphocyte

^Osteocalcin Osteopontin Alkaline Phosphatase

Bone

Monoblast

^Osteocalcin Osteopontin Alkaline Phosphatase

Bone

Monoblast

Effects of 1,25-dihydroxy-vitamin D3 (calcitriol) on bone. In addition to the effects on parathyroid cells, the kidney, and intestinal epithelium, calcitriol has direct effects on bone metabolism. Calcitriol can promote osteoclast differentiation and activity from monocyte precursor cells. Calcitriol also promotes osteoblast differentiation into mature cells. (From Holick [8]; with permission.)

DNA binding

Hinge region

Calcitiriol binding gly—asp 30

149 271

FIGURE 5-6

The vitamin D receptor (VDR). Within its target tissues, calcitriol binds to the VDR. The VDR is a 424 amino acid polypeptide. Its genomic information is encoded on the

12q12-14 chromosome, near the gene for the 1-a-hydroxylase enzyme. The VDR is found in the intestinal epithelium, parathyroid cells, kidney cells, osteoblasts, and thyroid cells. VDR also can be detected in keratinocytes, monocyte precursor cells, muscle cells, and numerous other tissues. The allele variations for the vitamin D receptor. Two allele variations exist for the vitamin D receptor (VDR): the b allele and the B allele. In general, normal persons with the b allele seem to have a higher bone mineral density [9]. Among patients on dialysis, those with the b allele may have higher levels of circulating parathyroid hormone (PTH) [7,9,10,11]. COOH—carboxy terminal; NH2—amino terminal. (From Root [7]; with permission.)

FIGURE 5-7

Mechanism of action of 1-25-dihydroxy-vitamin D3 (1,25(OH)2D3). 1,25(OH)2D3 is transported to the target cell bound to the vitamin D-binding protein (VDBP). The free form of 1,25(OH)2D3 enters the target cell and interacts with the vitamin D receptor (VDR) at the nucleus. This complex is phosphorylated and combined with the nuclear accessory factor (RAF). This forms a heterodimer, which then interacts with the vitamin D responsive element (VDRE). The VDRE then either promotes or inhibits the transcription of messenger RNA (mRNA) for proteins regulated by 1,25(OH)2D3, such as Ca-binding proteins, the 25-hydroxy-vita-min D3 24-hydroxylase enzyme, and parathyroid hormone. Pi—inorganic phosphate. (Adapted from Holick [8].)

FIGURE 5-8

PTH-like peptide (mw 16,000)

Nh 1

-2

-1 1 2

3

4

5

6

7

8

9

10

11

12

13

PTH

LYS

ARG SER VAL

SER

GLU

ILE

GLN

LEU

MET

HIS

ASN

LEU

GLY

LYS

PTH-like peptide

LYS

ARG ALA VAL

SER

GLU

HIS

GLN

LEU

LEU

HIS

ASP

LYS

GLY

Metabolism of parathyroid hormone (PTH). The PTH gene is located on chromosome 11p15. PTH messenger RNA (mRNA) is transcribed from the DNA fragment and then translated into a 115 amino acid-containing molecule of prepro-PTH. In the rough endoplasmic reticulum, this undergoes hydrolysis to a 90 amino acid-containing molecule, pro-PTH, which undergoes further hydrolysis to the 84 amino acid-containing PTH molecule. PTH is then stored within secretory granules in the cytoplasm for release. PTH is metabolized by hepatic Kupffer cells and renal tubular cells. Transcription of the PTH gene is inhibited by 1,25-dihydroxy-vitamin D3, calcitonin, and hypercalcemia. PTH gene transcription is increased by hypocalcemia, glucocorti-coids, and estrogen. Hypercalcemia also can increase the intracellular degradation of PTH. PTH release is increased by hypocal-cemia, ^-adrenergic agonists, dopamine, and prostaglandin E2. Hypomagnesemia blocks the secretion of PTH [7,12]. VDR— vitamin D receptor; VDRE—vitamin D responsive element. (Adapted from Tanaka and coworkers [12].)

FIGURE 5-9

Parathyroid-hormone-related protein (PTHrP). PTHrP was initially described as the causative circulating factor in the humoral hypercalcemia of malignancy, particularly in breast cancer, squamous cell cancers of the lung, renal cell cancer, and other tumors. It is now clear that PTHrP can be expressed not only in cancer but also in many normal tissues. It may play an important role in the regulation of smooth muscle tone, transepithelial Ca transport (eg, in the mammary gland), and the differentiation of tissue and organ development [7,13]. Note the high degree of homology between PTHrP and PTH at the amino end of the polypeptides. MW—molecular weight; N—amino terminal; C—carboxy terminal. (From Root [7]; with permission.)

614 - 671 - 684 -146 -171 - 829 - 829

O Cysteline # Conserved A Acidic

(pPKC phosphorylation site N-glycosylation

- Inactivating Arg186Gln Asp216Glu Tyr219Glu Glu298Lys Ser608Stop Ser658Tyr Gly670Arg Pro749Arg Arg796Trp Val818Ile -Stop Activating Glu128Ala

Cell membrane

Cell membrane

FIGURE 5-10

The calcium-ion sensing receptor (CaSR). The CaSR is a guanosine triphosphate (GTP) or G-protein-coupled polypeptide receptor. The human CaSR has approximately 1084 amino acid residues. The CaSR mediates the effects of Ca on parathyroid and renal tissues. CaSR also can be found in thyroidal C cells, brain cells, and in the gastrointestinal tract. The CaSR allows Ca to act as a first messenger on target tissues and then act by way of other second-messenger systems (eg, phospholipase enzymes and cyclic adenosine monophosphate). Within parathyroid cells, hypercalcemia increases CaSR-Ca binding, which activates the G-protein. The G-protein then activates the phospholipase C-|3-1-phosphatidylinosi-tol-4,5-biphosphate pathway to increase intracellular Ca, which then decreases translation of parathyroid hormone (PTH), decreases PTH secretion, and increases PTH degradation. The CaSR also is an integral part of Ca homeostasis within the kidney. The gene for CaSR is located on human chromosome 3q13 [3,4,7,14-16]. PKC—protein kinase C; HS—hydrophobic segment; NH2—amino terminal. (From Hebert and Brown [4]; with permission.)

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  • edda
    How act PTH and vitamin D in kidneys?
    21 days ago

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